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EP2751071B1 - Amides d'acide gras, compositions et procédés d'utilisation - Google Patents

Amides d'acide gras, compositions et procédés d'utilisation Download PDF

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EP2751071B1
EP2751071B1 EP12828585.5A EP12828585A EP2751071B1 EP 2751071 B1 EP2751071 B1 EP 2751071B1 EP 12828585 A EP12828585 A EP 12828585A EP 2751071 B1 EP2751071 B1 EP 2751071B1
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compound
fatty acid
ethyl
alkyl
amino
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EP2751071A4 (fr
EP2751071A2 (fr
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Jill C. Milne
Michael R. Jirousek
Jean E. Bemis
Chi B. Vu
Amal Ting
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Astria Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/40—Y being a hydrogen or a carbon atom
    • C07C323/41—Y being a hydrogen or an acyclic carbon atom
    • A—HUMAN NECESSITIES
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    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
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    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/20—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms

Definitions

  • Oily cold water fish such as salmon, trout, herring, and tuna are the source of dietary marine omega-3 fatty acids, with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) being the key marine derived omega-3 fatty acids.
  • Omega-3 fatty acids have previously been shown to improve insulin sensitivity and glucose tolerance in normoglycemic men and in obese individuals. Omega-3 fatty acids have also been shown to improve insulin resistance in obese and non-obese patients with an inflammatory phenotype. Lipid, glucose, and insulin metabolism have been shown to improve in overweight hypertensive subjects through treatment with omega-3 fatty acids.
  • Omega-3 fatty acids have also been shown to decrease triglycerides and to reduce the risk for sudden death caused by cardiac arrhythmias in addition to improve mortality in patients at risk of a cardiovascular event. Omega-3 fatty acids have also been taken as dietary supplements part of therapy used to treat dyslipidemia, and anti-inflammatory properties. A higher intake of omega-3 fatty acids lower levels of circulating TNF- ⁇ and IL-6, two of the cytokines that are markedly increased during inflammation processes ( Chapkin et al, Prostaglandins, Leukot Essent Fatty Acids 2009, 81, p. 187-191 ; Duda et al, Cardiovasc Res 2009, 84, p. 33-41 ).
  • DHA has also been shown to prevent breast cancer cell metastasis to bone in a mouse model utilizing MDA-MB-231 human breast cancer cells ( Mandal et al, Biochem. & Biophys. Res. Communications 2010, 402, p. 602-607 ).
  • Chronic oxidative stress and inflammation have now been linked to the development and progression of a number of debilitating diseases. Some of these diseases include renal failure, heart failure, atherosclerosis, osteoporosis, cancer, chronic obstructive pulmonary disease (COPD), Parkinson's disease and Alzheimer's disease.
  • COPD chronic obstructive pulmonary disease
  • Activation of the Nrf2 pathway in order to resolve this chronic oxidative stress and inflammation appears to be a particularly promising new therapeutic approach (For a review see Gozzelino, R. et al Annu. Rev. Pharmacol. Toxicol. 2010, 50, p. 323-54 ).
  • Nrf2 small molecule activators of Nrf2 have now been shown to be effective in the cisplatin-induced nephrotoxicity mouse model ( Aleksunes et al, J. Pharmacology & Experimental Therapeutics 2010, 335, p. 2-12 ), the transgenic Tg19959 mouse model of Alzheimer's disease ( Dumont et al, J. Neurochem. 2009, 109, p. 502-12 ), the mouse model for COPD ( Sussan, T. E. et al Proc. Natl. Acad. Sci. USA 2009, 106, p. 250-5 ), and the murine 4T1 breast tumor model ( Ling, X. et al Cancer Res. 2007, 67, p. 4210-8 ).
  • fatty acid amides There are many amines that can be covalently coupled with omega-3 fatty acids to produce fatty acid amides with improved biological activity.
  • the fatty acid amides disclosed herein have been designed to be stable in the plasma. However, in targeted tissues, intracellular enzymes will hydrolyze the fatty acid amides into the individual components, i.e. the omega-3 fatty acid and the amine moiety. In some embodiments, certain amine moieties do not necessarily display any significant biological activity. However, when these amines are coupled to an omega-3 fatty acid, the resulting fatty acid amides can be delivered into targeted tissues more efficiently to produce a biological effect that cannot be replicated by administering the fatty acid alone or in non covalent combination with the amine portion.
  • certain "PEGylated” amines are used to form fatty acid amides.
  • “PEGylation” is a common technique of incorporating polyethylene glycol (PEG) chains into a molecule to improve its hydrophobicity and pharmacokinetic profile ( Veronese et al Drug Discovery Today 2005, 10, p. 1451-8 ).
  • PEG polyethylene glycol
  • the resulting fatty acid amides can have an improved circulatory time and pharmacokinetic profile, in addition to being delivered into targeted tissues more efficiently than the corresponding acid.
  • the amine component itself displays significant biological activity.
  • the resulting fatty acid amides When these biologically active amines are coupled to an omega-3 fatty acid, the resulting fatty acid amides will produce a biological effect that cannot be replicated by administering the individual components or a noncovalent combination of the individual components.
  • the biological activity can be synergistic.
  • the side effects of the biologically active amines can be reduced since the individual components of the fatty acid amides are only released inside targeted tissues by hydrolysis involving various intracellular enzymes.
  • Non-limiting examples of biologically active amine components are cystamine, cysteamine, glucosamine, dexpramipexole, sapropterin, N-acylated cysteine, pencillamine, triethylenetetramine, 4-aminopyridine, fingolimod, and pramipexole.
  • Cysteamine has been used extensively to treat nephropathic cystinosis, an orphan genetic lysosomal storage disorder characterized by a massive accumulation of crystalline cystine within cells. Treatment of nephropathic cystinotic fibroblasts with cysteamine has been shown to significantly reduce the excess cystine present in these cells (For a review, see Gahl et al N. Engl. J. Med. 2002, 347, p. 111-121 ). Cystamine, the disulfide form of cysteamine, has also been found to be useful in reducing cystine level in nephropathic cystinotic fibroblasts ( Thoene et al Proc. Roy. Soc. Med. 1977, 70, Suppl. 3, p.
  • cysteamine and cystamine have been found to be neuroprotective in the YAC128 mouse model of Huntington's disease ( Van Raamsdonk et al J. Neurochem. 2005, 95, p. 210-220 ).
  • Fatty acid amide derivatives consisting of an omega-3 fatty acid that has been covalently liked to either cystamine or cysteamine can have an additional anti-inflammatory and neuroprotective effect that cannot be replicated by administering the individual components or the combination of the individual components.
  • Glucosamine has been used clinically to reduce the debilitating symptoms of osteoarthritis.
  • the anti-inflammatory properties of glucosamine can be partly attributed to the inhibition of prostaglandin E2 (PGE2) synthesis through the reduction of COX-2 ( Kapor et al J. Rheumatology 2012, 39, p. 635-644 ).
  • PGE2 prostaglandin E2
  • COX-2 Kapor et al J. Rheumatology 2012, 39, p. 635-644
  • treatment with glucosamine can also up-regulate the gene expression of heme oxygenase (HO-1), an important protective cellular mechanism toward reactive oxygen species ( Valvasan et al Rheumatology 2008, 47, p. 31-35 ).
  • Fatty acid/glucosamine amide derivatives created by covalently linking an omega-3 fatty acid to glucosamine via an amine linker group, can have synergistic activity along both the PGE2 pathway and the
  • Dexpramipexole is a low molecular weight, water-soluble compound that has recently been shown to be clinically effective in treating amyotrophic lateral sclerosis (ALS) ( Cudkowicz et al Nat. Med. 2011, 17, p. 1652-1657 ).
  • ALS patients treated with Dexpramipexole showed a dose-related slowing of symptom progression as well as increased survival time.
  • Preliminary studies into the mechanism of action appear to indicate that dexpramipexole can prevent mitochondrial ROS generation and thereby impart some neuroprotective effects ( Ferrari-Toninelli et al BMC Pharmacology 2010, 10, p. 1-6 ).
  • a covalent amide derivative between an omega-3 fatty acid and dexpramipexole can have a synergistic effect that cannot be duplicated by administering the individual components or a combination of the components.
  • Phenylketonuria is metabolic disorder that results from lack of enzymes that are needed to convert phenylalanine to tyrosine. If left untreated, the excessive buildup of phenylalanine can lead to mental retardation, speech impediments, seizures and behavioral abnormalities. Children with PKU often need supplementation with DHA for cognitive function and development. In patients with PKU, treatment with sapropterin has been shown to be effective in lowering blood level of phenylalanine. A fatty acid sapropterin amide can allow for more effective delivery of sapropterin to the liver where a high level of phenylalanine hydroxylase is expressed. In addition, with fatty acid sapropterin amides, DHA can also be delivered more effectively to cells to enhance cognitive function and development.
  • 4-Aminopyridine and fingolimod are amine containing compounds that have been found to be useful in treating relapsing remitting multiple sclerosis.
  • a covalent omega-3 fatty acid conjugate of 4-aminopyridine or fingolimod will have additional anti-inflammatory and neuroprotective effects that cannot be replicated by administering the individual components or the combination of the components.
  • N-acylated cysteine, tiopronin and penicillamine are some thiol containing compounds that have been used clinically to treat Wilson's disease, cystinuria and to thin the thick mucus present in cystic fibrosis patients. Fatty acid amide derivatives containing these thiol compounds will allow better tissue targeting and reduce side effects.
  • US 2011/082210 A1 discloses fatty acid fibrate derivatives and their use in the treatment of metabolic diseases.
  • US 2011/172240 A1 discloses fatty acid fumarate derivatives and their use in the treatment of cancer, metabolic disorders, and neurodegenerative disorders.
  • McCaughan et al. discloses ((((carboxamido)ethyl)disulfanyl)ethyl)carboxamides for use in the treatment of nephropathic cystinosis.
  • the invention is based in part on the discovery of fatty acid amides and their demonstrated effects in achieving improved treatment that cannot be achieved by administering the individual components (i.e. fatty acid and amine) or in noncovalent combination.
  • Fatty acid amides and compositions comprising them are useful in the treatment and prevention of diseases and disorders associated with inflammation.
  • the fatty acid amides described herein are useful in the treatment of autoimmune diseases such as rheumatoid arthritis, psoriasis, systemic lupus erythematosus, inflammatory bowel diseases (including colitis and Crohn's disease), respiratory diseases such as asthma, cystic fibrosis, COPD and neurodegenerative diseases such as multiple sclerosis, Huntington's disease, Parkinson's disease and Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS) and muscular dystrophy.
  • autoimmune diseases such as rheumatoid arthritis, psoriasis, systemic lupus erythematosus, inflammatory bowel diseases (including colitis and Crohn's disease), respiratory diseases such as asthma, cystic fibrosis, COPD and neurodegenerative diseases such as multiple sclerosis, Huntington's disease, Parkinson's disease and Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS)
  • any one or more of H may be substituted with a deuterium.
  • the invention also includes pharmaceutical compositions that comprise an effective amount of a fatty acid amide and a pharmaceutically acceptable carrier.
  • the compositions are useful for treating or preventing an autoimmune disease, respiratory disease, or neurodegenerative diseases.
  • the invention includes a fatty acid amide provided as a pharmaceutically acceptable salt, enantiomer, stereoisomer, or mixtures thereof.
  • Metabolic disorders are a wide variety of medical disorders that interfere with a subject's metabolism. Metabolism is the process a subject's body uses to transform food into energy. Metabolism in a subject with a metabolic disorder is disrupted in some way. Autoimmune diseases arise from an overactive immune response of the body against tissues normally present in the body. Neurodegenerative diseases result from the deterioration of neurons or their myelin sheaths, which would eventually lead to a variety of CNS-related dysfunctions. The fatty acid amides possess the ability to treat or prevent autoimmune, respiratory diseases, or neurodegenerative diseases.
  • aryl refers to cyclic, aromatic hydrocarbon groups that have 1 to 2 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc .), the aromatic rings of the aryl group may be joined at a single point ( e.g., biphenyl), or fused ( e.g., naphthyl).
  • the aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. The substituents can themselves be optionally substituted. It is understood that any of the substitutable hydrogens on an aryl can be substituted with halogen, C 1 -C 3 alkyl, hydroxyl, alkoxy and cyano groups.
  • C 1 -C 3 alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-3 carbon atoms. Examples of a C 1 -C 3 alkyl group include, methyl, ethyl, propyl and isopropyl.
  • C 1 -C 4 alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-4 carbon atoms. Examples of a C 1 -C 4 alkyl group include, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec -butyl and tert -butyl.
  • C 1 -C 5 alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-5 carbon atoms.
  • Examples of a C 1 -C 5 alkyl group include, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec -butyl and tert -butyl, isopentyl and neopentyl.
  • C 1 -C 6 alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-6 carbon atoms.
  • Examples of a C 1 -C 6 alkyl group include, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec -butyl, tert -butyl, isopentyl, and neopentyl. It is understood that any of the substitutable hydrogens on a C 1 -C 6 alkyl can be substituted with halogen, hydroxyl, alkoxy and cyano groups.
  • cycloalkyl refers to a cyclic hydrocarbon containing 3-6 carbon atoms.
  • examples of a cycloalkyl group include, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. It is understood that any of the substitutable hydrogens on a cycloalkyl can be substituted with halogen, C 1 -C 3 alkyl, hydroxyl, alkoxy and cyano groups.
  • heterocycle refers to a cyclic hydrocarbon containing 3-6 atoms wherein at least one of the atoms is an O, N, or S.
  • heterocycles include, aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, thiane, imidazolidine, oxazolidine, thiazolidine, dioxolane, dithiolane, piperazine, oxazine, dithiane and dioxane. It is understood that any of the substitutable hydrogens on a heterocycle can be substituted with halogen, C 1 -C 3 alkyl, hydroxyl, alkoxy and cyano groups.
  • heteroaryl refers to a monocyclic or bicyclic ring structure having 5 to 12 ring atoms wherein one or more of the ring atoms is a heteroatom, e.g. N, O or S and wherein one or more rings of the bicyclic ring structure is aromatic.
  • heteroaryl are pyridyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, tetrazolyl, benzofuryl, xanthenes and dihydroindole. It is understood that any of the substitutable hydrogens on a heteroaryl can be substituted with halogen, C 1 -C 3 alkyl, hydroxyl, alkoxy and cyano groups.
  • any one of the side chains of the naturally occurring amino acids means a side chain of any one of the following amino acids: Isoleucine, Alanine, Leucine, Asparagine, Lysine, Aspartate, Methionine, Cysteine, Phenylalanine, Glutamate, Threonine, Glutamine, Tryptophan, Glycine, Valine, Proline, Arginine, Serine, Histidine and Tyrosine.
  • fatty acid as used herein means an omega-3 fatty acid and fatty acids that are metabolized in vivo to omega-3 fatty acids.
  • fatty acids are all-cis -7,10,13-hexadecatrienoic acid, ⁇ -linolenic acid (ALA or all-cis -9,12,15-octadecatrienoic acid), stearidonic acid (STD or all-cis -6,9,12,15-octadecatetraenoic acid), eicosatrienoic acid (ETE or all-cis -11,14,17-eicosatrienoic acid), eicosatetraenoic acid (ETA or all-cis -8,11,14,17-eicosatetraenoic acid), eicosapentaenoic acid (EPA or all-cis- 5,8,11,14,17-eicosapentaenoic acid), docosapentaenoic acid (D
  • a “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus, and the terms “subject” and “patient” are used interchangeably herein.
  • the invention also includes pharmaceutical compositions comprising an effective amount of a fatty acid amide and a pharmaceutically acceptable carrier.
  • the invention includes a fatty acid amide provided as a pharmaceutically acceptable salt, enantiomers, stereoisomers, or mixtures thereof.
  • salts include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2, 2 - disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium
  • metabolic disease refers to disorders, diseases and syndromes involving dyslipidemia, and the terms metabolic disorder, metabolic disease, and metabolic syndrome are used interchangeably herein.
  • an "effective amount" when used in connection with a fatty acid amide is an amount effective for treating or preventing a metabolic disease.
  • carrier encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body.
  • treating refers to improving at least one symptom of the subject's disorder. Treating can be curing, improving, or at least partially ameliorating the disorder.
  • disorder is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • administer refers to either directly administering a compound or pharmaceutically acceptable salt of the compound or a composition to a subject, or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.
  • Boc and BOC are tert -butoxycarbonyl
  • Boc 2 O is di- tert -butyl dicarbonate
  • CDI is 1,1'-carbonyldiimidazole
  • DCC is N,N '-dicyclohexylcarbodiimide
  • DIEA is N,N- diisopropylethylamine
  • DMAP is 4-dimethylaminopyridine
  • DOSS sodium dioctyl sulfosuccinate
  • EDC and EDCI are 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • EtOAc is ethyl acetate
  • h is hour
  • HATU is 2-(7-aza-1 H benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
  • HPMC is hydroxypropyl methylcellulose, ox
  • a fatty acid amide according to Formula I is.
  • the fatty acids are selected from the group consisting of all-cis -7,10,13-hexadecatrienoic acid, ⁇ -linolenic acid, stearidonic acid, eicosatrienoic acid, eicosatetraenoic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid, docosahexaenoic acid (DHA), tetracosapentaenoic acid, tetracosahexaenoic acid, and lipoic acid.
  • the fatty acid is selected from eicosapentaenoic acid,docosahexaenoic acid, and lipoic acid. In other embodiments, the fatty acid is selected from eicosapentaenoic acid and docosahexaenoic acid. In some embodiments, the hydrolysis is enzymatic.
  • the present invention provides fatty acid amides according to Formula I: and pharmaceutically acceptable salts, enantiomers and stereoisomers thereof; wherein m, e, r, s, t, v, z, R 1 , R 2 , R 3 , R 4 , are as defined above for Formula I,
  • Z is and r is 2.
  • Z is and r is 3.
  • Z is and r is 7.
  • Z is and s is 3.
  • Z is and s is 5.
  • Z is and s is 6.
  • Z is and v is 1.
  • Z is and v is 2.
  • Z is and v is 6.
  • Z is and s is 3.
  • Z is and s is 5.
  • Z is and s is 6.
  • r is 2 and s is 6.
  • r is 3 and s is 5.
  • t is 1.
  • R 3 is H and R 4 is
  • R 3 is H and R 4 is
  • R 3 is H and R 4 is
  • R 3 is H and R 4 is
  • any one or more of H may be substituted with a deuterium.
  • Also provided in the invention is a compound of the invention for use in a method for inhibiting, preventing, or treating inflammation or an inflammatory disease in a subject, the inflammatory disease being selected from an autoimmune disease, an inflammatory respiratory disease, or a neurodegenerative disease.
  • the inflammatory disease being selected from an autoimmune disease, an inflammatory respiratory disease, or a neurodegenerative disease.
  • diseases include, but are not limited to: rheumatoid arthritis, asthma, adult respiratory distress syndrome, chronic obstructive airway disease, and cystic fibrosis; psoriasis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis and viral or autoimmune encephalitis.
  • the subject is administered an effective amount of a fatty acid amide.
  • the fatty acid amides can each be administered in amounts that are sufficient to treat or prevent a metabolic disease or prevent the development thereof in subjects.
  • Administration of the fatty acid amides can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.
  • compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • injectables tablets, suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices.
  • they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, all using forms well known to those skilled in the pharmaceutical arts.
  • Illustrative pharmaceutical compositions are tablets and gelatin capsules comprising a fatty acid amide and a pharmaceutically acceptable carrier, such as: a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; for tablets also;
  • Liquid, particularly injectable, compositions can, for example, be prepared by dissolution, dispersion
  • the fatty acid amide is dissolved in or mixed with a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form an injectable isotonic solution or suspension.
  • a pharmaceutically acceptable solvent such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like.
  • Proteins such as albumin, chylomicron particles, or serum proteins can be used to solubilize the fatty acid amides.
  • the fatty acid amides can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.
  • the fatty acid amides can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, containing cholesterol, stearylamine or phosphatidylcholines.
  • a film of lipid components is hydrated with an aqueous solution of drug to a form lipid layer encapsulating the drug, as described in United States Patent No. 5,262,564 .
  • Fatty acid amides can also be delivered by the use of monoclonal antibodies as individual carriers to which the fatty acid amides are coupled.
  • the fatty acid amides can also be coupled with soluble polymers as targetable drug carriers.
  • Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • fatty acid amide conjugates can be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
  • fatty acid amides are not covalently bound to a polymer, e.g., a polycarboxylic acid polymer, or a polyacrylate.
  • Parenteral injectable administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions or solid forms suitable for dissolving in liquid prior to injection.
  • compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1 % to about 80 %, from about 5 % to about 60 %, or from about 1 % to about 20 % of the fatty acid amide conjugate by weight or volume.
  • the dosage regimen utilizing the fatty acid amide is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal or hepatic function of the patient; and the particular fatty acid amide conjugate employed.
  • a physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Effective dosage amounts of the present invention when used for the indicated effects, range from about 20 mg to about 5,000 mg of the fatty acid amides per day.
  • Compositions for in vivo or in vitro use can contain about 20, 50, 75, 100, 150, 250, 500, 750, 1,000, 1,250, 2,500, 3,500, or 5,000 mg of the fatty acid amide.
  • the compositions are in the form of a tablet that can be scored.
  • Effective plasma levels of the fatty acid amide can range from about 5 ng/mL to 5000 ng/mL per day.
  • Appropriate dosages of the fatty acid amides can be determined as set forth in Goodman, L. S.; Gilman, A. The Pharmacological Basis of Therapeutics, 5th ed.; MacMillan: New York, 1975, pp. 201-226 .
  • Fatty acid amides can be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily.
  • fatty acid amides can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration can be continuous rather than intermittent throughout the dosage regimen.
  • Other illustrative topical preparations include creams, ointments, lotions, aerosol sprays and gels, wherein the concentration of the fatty acid amide conjugate ranges from about 0.1 % to about 15 %, w/w or w/v.
  • Fatty acid amides may also be administered with other therapeutic agents such as cholesterol-lowering agents, fibrates and hypolipidemic agents, DPP-IV inhibitors as anti-diabetic agents, anti-diabetic agents, antiepileptic agents, antiglaucoma agents, antihypertensive agents, anti-inflammatory agents, TNF- ⁇ inhibitors, anti-depressant agents, anti-cancer agents, immunosuppressant agents, agents to treat osteoporosis, and agents to treat multiple sclerosis.
  • the fatty acid amide can be co-administered with the other therapeutic agent.
  • the fatty acid amide can be administered before the other therapeutic agent.
  • the fatty acid amide can be administered after the other therapeutic agent.
  • the other therapeutic agent is a cholesterol-lowering agent.
  • cholesterol-lowering agents are atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe, and the combination of ezetimibe/simvastatin (Vytorin®).
  • the other therapeutic agent is a fibrate or hypolipidemic agent.
  • fibrates or hypolipidemic agents are acifran, acipimox, beclobrate, bezafibrate, binifibrate, ciprofibrate, clofibrate, colesevelam, gemfibrozil, fenofibrate, melinamide, niacin, and ronafibrate.
  • the other therapeutic agent is a DPP-IV inhibitor as anti-diabetic agent.
  • DPP-IV inhibitors as anti-diabetic agents are sitagliptin, saxagliptin, vildagliptin, linagliptin, dutogliptin, gemigliptin and alogliptin.
  • the other therapeutic agent is an Anti-diabetic agent.
  • anti-diabetic agents are acarbose, epalrestat, exenatide, glimepiride, liraglutide, metformin, miglitol, mitiglinide, nateglinide, pioglitazone, pramlintide, repaglinide, rosiglitazone, tolrestat, troglitazone, and voglibose.
  • the other therapeutic agent is an antiepileptic agent.
  • antiepileptic agents include Gabapentin, pregabalin.
  • the other therapeutic agent is an Antiglaucoma agents.
  • antiglaucoma agents include apraclonidine, befunolol, bimatroprost, brimonidine, brinzolamide, dapiprazole, dorzolamide, latanoprost, levobunolol, tafluprost, travoprost, and unoprostone isopropyl ester.
  • the other therapeutic agent is an antihypertensive agents.
  • antihypertensive agents include alacepril, alfuzosin, aliskiren, amlodipine besylate, amosulalol, aranidipine, arotinolol HCl, azelnidipine, bamidipine hydrochloride, benazepril hydrochloride, benidipine hydrochloride, betaxolol HCl, bevantolol HCl, bisoprolol fumarate, bopindolol, bosentan, budralazine, bunazosin HCl, candesartan cilexetil, captopril, carvedilol, celiprolol HCl, cicletanine, cilazapril, cinildipine, clevidipine, delapril, dilevalol, doxazosin mesylate,
  • the other therapeutic agent is an anti-inflammatory agent.
  • anti-inflammatory agents include celecoxib, rofecoxib, ibuprofen, naproxen, indomethacin, salicylic acid, salsalate, 5-aminosalicylic acid, dimethylfumarate, monomethyl fumarate, methotrexate, predisone, prednisolone, abatecept, aceclofenac, AF-2259, alefacept, amfenac sodium, ampiroxicam, amtolmetin guacil, arformoterol, bambuterol, bardoxolone methyl, butibufen, cankinumab, ciclesonide, deflazacort, doxofylline, dexibuprofen, droxicam, etodolac, flunoxaprofen, fluticasone propionate, fomoterol fumarate, golimumab, indacaterol, interferon-
  • the other therapeutic agent is a TNF- ⁇ inhibitor.
  • TNF- ⁇ inhibitors include infliximab, adalimumab, certolizumab, golimumab, and etanercept.
  • the other therapeutic agent is an anti-depressant agents.
  • anti-depressant agents include bupropion HCl, citalopram, desvenlafaxine, fluoxetine HCl, fluvoxamine maleate, metapramine, milnacipran, mirtazapine, moclobemide, nefazodone, paroxetine, pivagabine, reboxetine, setiptiline, sertraline HCl, tianeptine sodium, toloxatone and venlafaxine.
  • the other therapeutic agent is an anti-cancer agent.
  • anti-cancer agents include abarelix, alemtuzumab, alitretinoin,amrubicin HCl, amsacrine, anastrozole, arglabin, azacitidine, belotecan, bevacizumab, bexarotene, bicalutamide, bisantrene HCl, bortezomib, camostat mesylate, capecitabine, catumaxomab, cetuximab, cladribine, clofarabine, cytarabine ocfosfate, dasatinib, degarelix acetate, denileukin diftitox, doxetaxel, doxifluridine, enocitabine, epirubicin HCl, erlotinib, exemestane, fludarabine phosphate, flutamide, formestane
  • the other therapeutic agent is an immunosuppressant agent.
  • immunosuppressant agents include cyclosporine, everolimus, gusperimus, mizoribine, muromonab-CD3, mycophenolate sodium, mycophenolate mofeti, pimecrolimus, tacrolimus.
  • the other therapeutic agent is an agents to treat osteoporosis.
  • agents to treat osteoporosis include alendronate sodium, ibandronic acid, incadronic acid, raloxifene HCl, risdronate sodium, strontium ranelate.
  • the other therapeutic agent is an agent to treat multiple sclerosis.
  • agents to treat multiple sclerosis include dimethyl fumarate, mono methyl fumarate, fingolimod, teriflunomide, laquinimod, cladribine, interferon beta-1a, betaseron, glatimer acetate, natalizumab.
  • a fatty acid of the general formula A can be coupled directly with an amine of the general formula B using any standard amide coupling reagent such as EDCI, HATU or DCC, in an organic solvent such as CH 2 Cl 2 or acetonitrile.
  • Any standard amide coupling reagent such as EDCI, HATU or DCC
  • organic solvent such as CH 2 Cl 2 or acetonitrile.
  • amines of the formula B is commercially available. wherein r, s and m are as defined above.
  • a fatty acid of the general formula A can be coupled directly with an amine of the general formula D using any standard amide coupling reagent such as EDCI, HATU or DCC, in an organic solvent such as CH 2 Cl 2 or acetonitrile.
  • amide coupling reagent such as EDCI, HATU or DCC
  • organic solvent such as CH 2 Cl 2 or acetonitrile.
  • m 1, 2, 3, 4, 5 and 6
  • primary amines such as the ones shown below (all commercially available) can be used for the same amide coupling reaction: wherein e, r, and s are as defined above.
  • the commercially available amine F can be coupled with a BOC-protected amino acid of the formula G using EDC or HATU to afford an intermediate amide.
  • the BOC protecting group can be removed by treatment with acid such TFA or HCl to afford compounds of the general formula H.
  • This amine can be coupled with a fatty acid of the general formula A to obtain compounds of the general formula I.
  • any other amines such as the ones shown in Scheme 3 can be used for the same sequence of reactions. wherein r and s are as defined above.
  • the commercially available amine J is treated with a reagent such as BOC-anhydride to obtain the BOC-protected derivative K.
  • a reductive amination using propylamine in the presence of either sodium triacetoxyborohydride or sodium cyanoborohydride affords compound L, a differentially protected diamine intermediate.
  • Intermediate L can be coupled with a fatty acid of the formula A in the presence of HATU and a tertiary amine such as DIEA or Et 3 N, followed by treatment with HCl to afford compound M.
  • e, r and s are as defined above.
  • this scheme illustrates the use of differential protecting group to enable amide coupling reaction at one of the two amino sites.
  • the BOC-protected amine L can be treated with a reagent such as FMOC-Cl according to the procedures outlined in Greene's Protective Groups in Organic Synthesis, Wiley, 3rd Editi on.
  • the resulting Fmoc-protected compound can be treated with acids such as TFA or HCl to afford compound N.
  • Compound N can be coupled with a fatty acid of the formula A , followed by treatment with a base such as morpholine or diethylamine to obtain compounds of the general formula O.
  • compound N can also be subjected to the same reaction sequence outlined in Scheme 3 using the BOC-protected amino acid of the formula G to eventually obtain compounds of the general formula P. whewherein r and s are as defined above.
  • Scheme 6 illustrates the use of protecting groups to differentiate a polyamine.
  • the fatty acid of the formula A is coupled with ethanolamine to obtain compounds of the general formula Q.
  • the alcohol group can be oxidized to the corresponding aldehyde using reagents such as pyridinium dichromate or Dess-Martin reagent to obtain compounds of the general formula R.
  • the acylated amine of the formula S can be prepared using the procedures outlined in Andruszkiewicz et al. Synthetic Commun. 2008, 38, 905-913 .
  • Compound R and S can be reacted under reductive amination conditions using either sodium borohydride or sodium cyanoborohydride to obtain compounds of the general formula T.
  • Treatment of T with a fluoride reagent will selectively remove the silyl protecting group and treatment with an acid such as TFA or HCl will remove the remaining BOC protecting group to afford compounds of the general formula U.
  • Nephropathic cystinosis is an orphan genetic lysosomal storage disorder characterized by a massive accumulation of crystalline cystine within cells. Affected individuals develop a proximal renal tubulopathy and progress, if untreated, to end-stage renal failure.
  • Omran et al (Bioorg. Med. Chem. 2011, p, 3492 ) described a convenient in vitro system to quickly evaluate compounds that could deplete levels of cystine in cultured fibroblasts. Cystinotic fibroblasts (cell line GM00008, Coriell Cell Repository) were seeded in a 6-well plate and grown in DMEM/15% FBS until confluent.
  • the compound of the invention was formulated in 100% ethanol at a concentration of 50 mM; prior to addition to cells, drugs were further diluted in 100% FBS and sonicated for one hour. Cells were incubated with drug for 24 hours, then harvested via trypsinization. Cells were subsequently washed in PBS and suspended in a 3:1 solution of 5.2 mM N-ethylmaleimide (Sigma) to 12% sulfosalicylic acid (Sigma) in order to derivatize free cysteine and precipitate protein respectively. To lyse cells, samples were then frozen at -80 degrees Celsius, thawed, and sonicated twice for 1 minute. Lysates were cleared of precipitated protein via centrifugation and samples were subsequently processed for LC-MS/MS analysis.
  • Protein quantification was accomplished by dissolving precipitated protein in 0.25 M NaOH and 1 M Tris (pH 7.5), and spectrophotometric measurement using the Bradford method.
  • Compound I-9 was evaluated in this cystinotic fibroblast assay.
  • the level of cystine in this cystinotic cell line was quantitated by LC-MS/MS. A depletion of cystine was observed when cystinotic fibroblasts were treated with 50 ⁇ M of compound I-9.
  • the level of cystine was expressed as the percentage of control (POC). Using this method, compound I-9 showed a 68% reduction in the cystine level at 50 ⁇ M, whereas the control compound cysteamine showed a 45% reduction in the cystine level at 50 ⁇ M.
  • the cystine level was determined as follows: To the 50 ⁇ L of supernatant, acetonitrile (400 ⁇ L) containing 200ng/ml Internal standard (deuterated cystine) was added and mixture was vortexed for 1 min followed by centrifugation for 10 minutes. Supernatant was transferred to a clean LC vials and 10 ⁇ l of the sample was injected on LC-MS/MS for the measurement of Cystine.
  • Cystine was measured by LC-MS/MS. 10 ⁇ l of the sample was injected into the column (Luna, HILIC, 150X4.60mm, 3 ⁇ Phenomenex). Cystine and deuterated cystine was eluted from the column by a stepwise gradient of 10% mobile phase B at 0 min, 10% B at 2.5 min, 50% B at 2.7 min and 10% B at 3 min. Mobile phase A contained Acetonitrile/Water/Ammonium acetate (20mM) with 0.1% Formic acid and mobile phase B contained Acetonitrile/Ammonium acetate (20mM) with 0.1% formic acid. The column elute was directly injected into a Agilent triple quad, which was maintained in electrospray positive mode.
  • Cystine and the internal standard was 2.25 min. Cystine was monitored via the transition m/z 241.3-152 with a fragmentor of 75 and collision energy of 7Ev and duterated cystine was monitored via the transition m/z 247.3-124.1 with a fragmentor 126 and collision energy of 9eV. The column was maintained at 25°C.
  • Nephropathic cystinosis is an orphan genetic lysosomal storage disorder characterized by a massive accumulation of crystalline cystine within cells. The accumulation of cysteine is due to a defective lysosomal cystine transporter called cystinosin.
  • cystinosin A genetic mouse model lacking cystinosin has recently been described ( Cherqui et al Molecular and Cellular Biology 2002, 22, p. 7622-7632 ). Mice lacking cystinosin have been shown to have a substantial increase in cystine level in numerous tissues including liver, kidney, spleen, muscle, brain and heart.
  • mice lacking cystinosin with cysteamine at 200 or 400 mg/kg orally for 7, 30 or 60 days has been shown to reduce cystine levels of all tissues tested, with the greatest effect observed in the liver and kidney, after 60 days.
  • Compounds described herein can be evaluated in a similar fashion for their ability to reduce cystine levels in certain tissues using this genetic mouse model lacking cystinosin.
  • Transgenic Huntington disease mice expressing highly expanded human huntingin (YAC128) and their wild type littermates can be used to assess the effect of bis-fatty acid conjugates containing cystamine on transglutamine levels.
  • Three-month old YAC mice are treated with the desired conjugate for a period of two weeks before being sacrificed.
  • Mice are asphyxiated with carbon dioxide and the brains are immediately removed, separated into forebrain and hindbrain, frozen in isopentane on dry ice and stored at -80 °C. Tissues are then processed to measure transglutaminase activity as well as to assess striatal neuropathology according to the detailed procedure outlined in Van Raamsdock, J. M. et al, J. Neurochemistry 2005, 95, p. 210-220 .
  • Transgenic animals that are 7 months of age can also be used to assess for motor functions (such as time on rotarod) when administered with compounds of this invention over a period of 4 months.
  • HepG2 cells are seeded at 25,000 cells per well in collagen-coated 96-well plates in growth media (DMEM with 10% fetal bovine serum). The following day, fatty acid amides are complexed to lipoprotein-deficient fetal bovine serum at the appropriate concentration. Growth media is then removed from and the HepG2 cells are washed once with PBS. The lipoprotein-deficient FBS with the complexed fatty acid amide conjugates is added to DMEM for a final 10% concentration. Each concentration of fatty acid amide is tested in triplicate. Cells are incubated for 16 hours with the fatty acid amide. Alamar Blue® (Invitrogen) is then added to the media to determine cell viability per the manufacturer's instructions.
  • DMEM collagen-coated 96-well plates in growth media
  • fatty acid amides are complexed to lipoprotein-deficient fetal bovine serum at the appropriate concentration. Growth media is then removed from and the HepG2 cells are washed once with
  • HepG2 cells are seeded at 20,000 cells per well in 96 well plates. After adhering overnight, growth media (10% FBS in DMEM) is removed and cells are serum starved for 24 hours in DMEM containing 1% fatty acid free bovine serum albumin (BSA, Sigma). Cells are then treated with the fatty acid amides at a final concentration of 50 ⁇ M in 1% BSA or 0.1 oleate complexed to fatty acid free BSA in a 5:1 molar ratio. Cells are incubated for 6 hours and then washed with PBS. RNA was reverse-transcribed using the cells II cDNA reagents according to standard protocols (outlined in Applied Biosystem StepOne Real-time PCR protocols).
  • Real time PCR of transcripts can be performed with Tagman assays for the three specific genes FASN (fatty acid synthase), SCD (steroyl CoA desaturase) and ApoA1(apolipoprotein A1). In all three cases, 18S-VIC® is used as a normalization control.
  • mice Male Zucker rats ( HsdHlr:ZUCKER-Lepr ⁇ fa) between 8-10 weeks of age are purchased from Harlan.
  • Zucker rats are maintained on Teklad Global Rodent Diet (2018S) during the acclimation period and for the duration of study.
  • the Zucker rats are weighed and randomly assigned to treatment arms based on body weight and plasma TG levels (n is 8). Inclusion criteria for the study include body weight >300 grams and fed TG levels in plasma >800 mg/dL.
  • Rats are randomized into treatment arms based on pre-dose (day -1) body weights and plasma levels (fed) of triglycerides. Dosing is initiated on day 1 and continue through day 5. Dosing is daily (qd) by oral gavage (po) for all treatment arms.
  • Body weights are measured for all rats on days 1 through 5.
  • a blood sample (fed) are collected from each rat, processed for plasma and stored at -80°C.
  • food are removed from all rats to initiate fasting state.
  • rats are dosed at 8am according to treatment arm. Two hours later (10am) two blood draws from each rat are collected and processed for plasma. Triglyceride levels are then analyzed by standard protocols using commercially available kits.
  • Golden Syrian Hamster (Strain: HsdHanTM:AURA, from Harlan Laboratories), 5-6 weeks of age, with a body weight of approximately 80 g, are used for the study.
  • the Hamsters are maintained on high fat diet D12492 (Research Diets, New Brunswick NJ) during the acclimation period and throughout the study. Animals will then receive drinking water supplemented with 10% fructose (Sigma, supplied by Catabasis) starting on day -8 and continuing throughout the study.
  • the hamsters will be randomized into treatment arms based on pre-dose (day -1) body weights and plasma levels (fed) of triglycerides (TG). Dosing will be initiated on day 1 and continue through day 28.
  • Dosing will be daily (qd) by oral gavage (po) for all treatment arms. On day 27, hamsters will be fasted at the beginning of the dark cycle. Hamsters will be dosed at 8am on day 28 according to the treatment arm. Two hours later (10am) a blood sample will be collected from each hamster, processed to plasma and stored at -80°C. Triglyceride and HDL cholesterol levels will be determined using standard protocols and the commercially available kits from Abcam, Cayman or Sigma-Aldrich.
  • RAW 264.7 cells stably expressing a 3x NF- ⁇ B response elemement-drive luciferase reporter were seeded into 96 well plates in sera-free medium (Optimem) 18 hours prior to compound application.
  • Compounds of the invention were prepared by first making 100 mM stock solutions in EtOH. Stock solutions were then diluted 1:100 in low LPS FBS (Gemini BenchMark 100-106), mixed vigorously and allowed to incubate at room temperature for 30 minutes.
  • Table 1 summarizes the IC50 values for a number of fatty acid amides in this NF- ⁇ B luciferase reporter assay.
  • a (-) indicates that the compound showed no inhibitory activity up to 200 ⁇ M.
  • a (+) indicates that the compound showed inhibitory activity of less than 200 ⁇ M.
  • a (+ +) indicates that the compound showed inhibitory activity of less than 50 ⁇ M.
  • Table 1. Summary of IC50 values for fatty acid amides in the NF- ⁇ B luciferase reporter assay.
  • Compound NF-kB inhibitory activity IC 50 ⁇ M DHA - EPA - I-21 + I-47 - I-48 ++ I-49 ++ I-52 ++ I-57 ++
  • RAW264.7 macrophages were seeded at a density of 100,000 cells/well in a 96-well plate in DMEM supplemented with 10% FBS and Penn/strep. 16 hours later, medium was aspirated and replaced with 90 ⁇ L/well of serum-free DMEM.
  • Fatty acid amides were brought up in 100% EtOH to a concentration of 100mM and then diluted 1:100 in 100% FBS for a stock solution consisting of ImM compound and 1% EtOH. These stock solutions were then diluted 1:10 in FBS supplemented with 1% EtOH to generate a 100 ⁇ M of the fatty acid amide.
  • IL-1 ⁇ transcript levels were then measured using Taqman primer/probe assay sets (Applied Biosystems), normalized to GAPDH using the deltaCt method, and the data expressed relative to vehicle only control.
  • Figure 1 summarizes the IL-1 ⁇ gene expression data on compound I-57 (cellular toxicity was assessed using alamar blue as indicator, abbreviated in the figure as AB). As shown in this figure, upon dosing with compound I-57 , there was a decrease in the gene expression of the inflammatory cytokine IL-1 ⁇ .
  • RAW264.7 macrophages were seeded at a density of 100,000 cells/well in a 96-well plate in DMEM supplemented with 10% FBS and Penn/strep. 16 hours later, medium was aspirated and replaced with 90uL/well of serum-free DMEM.
  • Fatty acid amides were brought up in 100% EtOH to a concentration of 100mM and then diluted 1:100 in 100% FBS for a 20x stock solution consisting of ImM compound and 1% EtOH.
  • the fatty acid amide 20x stock solutions were diluted 1:2 in FBS supplemented with 1% EtOH for a 500uM 10x stock solution.
  • the 10x stock solutions were then serially diluted 1:2 in FBS supplemented with 1% EtOH and 10 ⁇ L of each dilution was added to the RAW246.7 cells to generate final concentrations of 50, 25, 12.5, 6.25, 3.12 and 1.6 ⁇ M.
  • the compounds were allowed to pre-incubate for 2 hours before stimulation of 100ng/ml LPS (10 ⁇ L of 1 ⁇ g/ml LPS is added to each well). Following 3 hours of LPS stimulation, cells were washed once in 1x PBS, aspirated dry, and flash frozen in liquid nitrogen. RNA was then isolated and converted to cDNA using the Cells to cDNA kit (Ambion) according to the manufacturer's protocol.
  • mice Female Sprague-Dawley rats (8 weeks old, with an average weight of 150 g) are used for the study. Diabetes is induced by a single tail vein injection of streptozotocin (STZ) in 0.1 mol/L sodium citrate buffer, pH 4.5. Diabetes is then confirmed by measuring blood glucose levels at two and three days after the STZ treatment. Diabetic animals are classified as those with plasma glucose higher than 16 nmol/L. The diabetic animals are then divided into the vehicle control group and the treatment group (each group having 12 animals). All animals are housed individually with a light dark cycle of 12 hours each, with animals having free access to food and water.
  • STZ streptozotocin
  • diabetic animals are treated with 3 IU of ultralente insulin three times per week in the afternoon (at approximately 3 to 4 pm).
  • the dose of insulin is increased to 5 IU at week 15.
  • Animals are dosed with the vehicle or the fatty acid amide over a 28 week period (Examples of vehicles that can be used include combinations of solvents such as polyethylene glycol and propyleneglycol, lipids such as glycerol monooleate and soybean oil, and surfactants such as polysorbate 80 and cremophor EL).
  • solvents such as polyethylene glycol and propyleneglycol
  • lipids such as glycerol monooleate and soybean oil
  • surfactants such as polysorbate 80 and cremophor EL.
  • Progression of renal disease can be assessed by monthly measurements of urinary albumin and plasma creatinine concentrations.
  • Urinary albumin can be quantified by a competitive ELISA assay according to the protocols outlined in Degenhardt et al, Kidney International 2002, 61, p. 939-950 .
  • Plasma creatinine concentrations can be measured by the Jaffé picric acid procedure, using the standard kit from Sigma (Sigma cat # 555-A).
  • Statistical analyses can be performed using SigmaStat for Windows V1.00.
  • P values can be calculated by non-parametric Mann-Whitney Rank Sum analysis.
  • dyslipidemia can also be assessed by measuring plasma triglycerides and total cholesterol.
  • Plasma lipids can be measured by enzymatic, colorimetric, end-point assays using standardized, commercially available kits.
  • Total cholesterol can be analyzed using the Sigma kit (cat # 352) and triglycerides can be analyzed by the Sigma kit (cat # 37, GOP Grinder).
  • mice 10 to 12-week old male C57BL/6 mice of approximately 30 g in body weight are used. After the normal acclimation period, the animals are maintained on a standard diet and water is freely available. Mice are then given a single intraperitoneal injection of either the vehicle or cisplatin (20 mg/kg, at a concentration of 1 mg/mL in saline). Ten animals are used per treatment group. For the drug treatment group, beginning 24 hours prior to the cisplatin injection, animals are dosed with a fatty acid amide (formulated in combinations of solvents such as polyethylene glycol and propyleneglycol, lipids such as glycerol monooleate and soybean oil, and surfactants such as polysorbate 80 and cremophor EL).
  • solvents such as polyethylene glycol and propyleneglycol
  • lipids such as glycerol monooleate and soybean oil
  • surfactants such as polysorbate 80 and cremophor EL.
  • TNF- ⁇ in serum can be determined using a commercially available enzyme-linked immunosorbent assay (ELISA). Tissues are processed for histology and RNA isolation. Tubular injury can be assessed in PAS-stained sections using a semi-quantitative scale described in " G. Ramesh and W. B. Reeves, Kidney International, 2004, 65, p. 490-498 ".
  • tert-butyl (2-((2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)ethyl)disulfanyl)ethyl)carbamate was prepared according to the procedures outlined in WO 2011106688 .
  • tert-butyl (2-((2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenamido)ethyl)disulfanyl)ethyl)carbamate was prepared according to the procedures outlined in WO 2011106688 .
  • Glyceric acid was readily available commercially as an aqueous solution.
  • the calcium salt of glyceric acid was isolated as follows: to a mixture of glyceric acid (20% in water) (50 g, 94.33 mmol) in H 2 O (20 mL) was added Ca(OH) 2 (3.49 g, 47.16 mmol). The mixture was stirred at room temperature for 2 hours and then liophilized to afford 11.8 g of the calcium salt of glyceric acid.
  • the calcium salt of glyceric acid (4.81 g, 38.53 mmol) was taken up in 100 mL of DMF along with HOBt (6.5 g, 48.16 mmol), EDCI (9.23 g, 48.16 mmol), (5Z,8Z,11Z, 14Z,17Z)-N-(2-((2-aminoethyl)disulfanyl)ethyl)icosa-5,8,11,14,17-pentaenamide (14 g, 32.11 mmol) and DMAP (7.77 g, 64.22 mmol). The resulting reaction mixture was stirred at room temperature overnight.
  • Glucosamine-HCl salt ((2R,3R,4R,5S,6R)-3-amino-6-(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol hydrochloride, 500mg, 2.32 mmol) was pre-stirred in 3 mL CH 2 Cl 2 and triethylamine (468 ul, 1.5 equivalents). Next, N-Boc- L -alanine ((S)-2-((tert-butoxycarbonyl)amino)propanoic acid, 439 mg, 1.0 equivalents) and EDC (672 mg, 1.5 equivalents) were added. The reaction was stirred at room temperature overnight under N 2 until completion.
  • the precipitated material was collected by filtration and washed with reagent grade alcohol (120 mL), followed by heptanes (100 mL). The resulting solids were dried under high vacuum for 2 h and then taken up in 50 mL of ethanol and cooled to between 0 and 5 °C. With continuous stirring, concentrated HCl (45 mL) was slowly added to the reaction while maintaining the temperature at between 0 and 5 °C, and the mixture was stirred for an additional 15 min. Methyl t-butyl ether (MTBE, 270 mL) was added to mixture, and stirring was continued for additional 1.5 h at this temperature.
  • MTBE Methyl t-butyl ether

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Claims (9)

  1. Composé de formule I :
    Figure imgb0157
     ou un sel, un énantiomère ou un stéréoisomère pharmaceutiquement acceptables de celui-ci ;
    dans lequel
    Z est
    Figure imgb0158
     ou
    Figure imgb0159
    chaque r est indépendamment 2, 3, ou 7 ;
    chaque s est indépendamment 3, 5, ou 6 ;
    chaque t est indépendamment 0 ou 1 ;
    chaque v est indépendamment 1, 2, ou 6 ;
    R1 et R2 sont indépendamment -H, -D, -alkyle en C1-C4, -halogène, -OH, -C(O) (alkyle en C1-C4) , -O-aryle, -O-benzyle, -OC(O) (alkyle en C1-C4), -alcène en C2-C3, -alcyne en C2-C3, -NH2, -NH (alkyle en C1-C3), -N (alkyle en C1-C3)2, -NH(C(O) (alkyle en C1-C3)), -N(C(O) (alkyle en C1-C3))2, -SH, -S (alkyle en C1-C3), -S(O) (alkyle en C1-C3), ou -S(O)2 (alkyle en C1-C3) ;
    R3 est H
    et R4 est sélectionné dans le groupe constitué par
    Figure imgb0160
    Figure imgb0161
     et
    Figure imgb0162
     dans lequel
    R est un groupe -alkyle en C1-C6 non substitué linéaire ou ramifié ; ou
    un composé sélectionné parmi
    Figure imgb0163
     et
    Figure imgb0164
     ou un sel pharmaceutiquement acceptable de celui-ci.
  2. Composé selon la revendication 1, dans lequel le composé est
    Figure imgb0165
     ou un sel pharmaceutiquement acceptable de celui-ci.
  3. Composé selon la revendication 1, dans lequel le composé est
    Figure imgb0166
     ou un sel pharmaceutiquement acceptable de celui-ci.
  4. Composé selon la revendication 1, dans lequel le composé est
    Figure imgb0167
     ou un sel pharmaceutiquement acceptable de celui-ci.
  5. Composé selon la revendication 1, dans lequel le composé est
    Figure imgb0168
     ou un sel pharmaceutiquement acceptable de celui-ci.
  6. Composé selon la revendication 1, dans lequel le composé est
    Figure imgb0169
     ou un sel pharmaceutiquement acceptable de celui-ci.
  7. Composé selon la revendication 1, dans lequel le composé est
    Figure imgb0170
     ou un sel pharmaceutiquement acceptable de celui-ci.
  8. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 7 et un excipient pharmaceutiquement acceptable.
  9. Composé selon l'une quelconque des revendications 1 à 7 ou la composition pharmaceutique selon la revendication 8 pour son utilisation dans le traitement d'une maladie auto-immune, d'une maladie respiratoire inflammatoire, ou d'une maladie neurodégénérative, de préférence dans lequel la maladie auto-immune est sélectionnée parmi la mucoviscidose, la polyarthrite rhumatoïde, le psoriasis, le lupus érythémateux systémique, et une affection abdominale inflammatoire, ou dans lequel la maladie respiratoire inflammatoire est sélectionnée parmi l'asthme, le syndrome de détresse respiratoire de l'adulte, une maladie chronique obstructive des voies respiratoires, la BPCO et la mucoviscidose, ou dans lequel la maladie neurodégénérative est sélectionnée parmi la sclérose en plaques, la maladie de Parkinson, la maladie d'Alzheimer, la chorée d'Huntington, la sclérose latérale amyotrophique (SLA) et la dystrophie musculaire.
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WO2016086136A1 (fr) * 2014-11-26 2016-06-02 Catabasis Pharmaceuticals, Inc. Conjugués de cystéamine d'acide gras de modulateurs de cftr et leur utilisation dans le traitement de troubles médicaux
MA41031A (fr) * 2014-11-26 2017-10-03 Catabasis Pharmaceuticals Inc Conjugués cystéamine-acide gras et leur utilisation comme activateurs de l'autophagie
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WO2011044136A1 (fr) * 2009-10-05 2011-04-14 Catabasis Pharmaceuticals, Inc. Dérivés d'acipimox d'acide gras et leurs utilisations
US20110082202A1 (en) * 2009-10-05 2011-04-07 Milne Jill C Fatty acid acifran derivatives and their uses
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